This invention relates to a process for resolving (R)-2-benzylsuccinic acid 4-[4-(N-t-butoxycarbonyl-methylamino)-piperidine]amide. (R)-2-benzylsuccinicacid4-[4-(N-t-butoxycarbonyl-methylamino)-piperidine] amide is an intermediate in the synthesis of theorally active renin inhibitor 4-[4-(N-methylamino )piperidine ]-(R)-2-benzylsuccinamide-(SMe)cystein-nor-cyclostatine hydrochloride, which is an an antihypertensive agent.
Renin is a proteolytic enzyme which is known to be active in vivo in cleaving the naturally occuring plasma glycoprotein angiotensinogen. In the case of human angiotensinogen, renin cleaves the bond between the leucine (10th) and valine (11th) amino acid residues at the N-terminal end of the angiotensinogen. The circulating N-terminal decapeptide known as angiotensin I that is formed by the cleaving action of renin is subsequently broken down by the body to an octapeptide known as angiotensin II. Angiotensin II is known to be a potent pressor substance , i.e., a substance that is capable of inducing a significant increase in blood pressure and is believed to act by causing the constriction of blood vessels and the release of the sodium retaining hormone aldosterone from the adrenal gland. The renin-angiotensinogen system has been implicated as a causative factor in certain forms of hypertension and congestive heart failure. The renin inhibitors that can be made from the compounds of the invention alleviate the adverse effects of the functioning renin-angiotensinogen system by inhibiting the angiotensinogen cleaving action of renin.
The renin inhibitors that can be prepared from the intermediates of this invention are described in U.S. patent application Ser. No. 08/028,038, which was filed on Mar. 8, 1993. U.S. patent application Ser. No. 08/028,038 also describes the pharmacology of 4-[4-(N-methylamino)piperidine]-(R)-2-benzylsuccinamide-(SMe)cysteine-norc yclostatine hydrochloride.